The association of circulating amylin with β‐amyloid in familial Alzheimer's disease

Ly, Han; Verma, Nirmal; Sharma, Sanjeev; Kotiya, Deepak; Despa, Sanda; Abner, Erin L.; Nelson, Peter T.; Jicha, Gregory A.; Wilcock, Donna M.; Goldstein, Larry B.; Guerreiro, Rita; Brás, José; Hanson, Angela J.; Craft, Suzanne; Murray, Andrew J.; Biessels, Geert Jan; Troakes, Claire; Zetterberg, Henrik; Hardy, John; Lashley, Tammaryn; Aesg,; Despa, Florin

doi:10.1002/trc2.12130

Cited by 27 publications

(75 citation statements)

References 31 publications

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“…However, we found the presence of IAPP in brain sections from AD patients, but not that from non-AD subjects. This is consistent with the previous reports that IAPP is detected in the brain parenchyma and CSF of AD patients [ 32 , 33 ]. We detected no IAPP mRNA expression in the AD brain, suggesting IAPP in the brain is from the peripheral system.…”

Section: Discussionsupporting

confidence: 94%

“…Likewise, compounds inhibiting the aggregation and/or stimulating the elimination of IAPP aggregates in T2DM may have the potential to treat AD [ 44 ]. Indeed, suppressing the secretion of amylin protected a rodent model against AD-associated phenotypes [ 33 ]. Moreover, treatment with the IAPP receptor antagonist has been shown to improve cognitive functions and reduce AD pathology in mouse models of AD [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

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Islet amyloid polypeptide cross-seeds tau and drives the neurofibrillary pathology in Alzheimer’s disease

Zhang

Meng

Wang

et al. 2022

Mol Neurodegeneration

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Background The pathologic accumulation and aggregation of tau is a hallmark of tauopathies including Alzheimer’s disease (AD). However, the molecular mechanisms mediating tau aggregation in AD remain elusive. The incidence of AD is increased in patients with type 2 diabetes (T2DM), which is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. However, the molecular mechanisms bridging AD and T2DM remain unknown. Methods We first examined the presence of IAPP in the neurofibrillary tangles of AD patients. Then we tested the effect of IAPP on tau aggregation. The biochemical and biological characteristics of the IAPP-tau fibrils were tested in vitro. The seeding activity and neurotoxicity of the IAPP-tau fibrils were confirmed in cultured neurons. Lastly, the effect of IAPP on tau pathology and cognitive impairments was determined by injecting the IAPP-tau fibrils and IAPP fibrils into the hippocampus of tau P301S mice. Results We found that IAPP interacts with tau and accelerates the formation of a more toxic strain, which shows distinct morphology with enhanced seeding activity and neurotoxicity in vitro. Intrahippocampal injection of the IAPP-tau strain into the tau P301S transgenic mice substantially promoted the spreading of tau pathology and induced more severe synapse loss and cognitive deficits, when compared with tau fibrils. Furthermore, intracerebral injection of synthetic IAPP fibrils initiated tauopathy in the brain of tau P301S transgenic mice. Conclusions These observations indicate that IAPP acts as a crucial mediator of tau pathology in AD, and provide a mechanistic explanation for the higher risk of AD in individuals with T2DM.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Islet amyloid polypeptide cross-seeds tau and drives the neurofibrillary pathology in Alzheimer’s disease

Zhang

Meng

Wang

et al. 2022

Mol Neurodegeneration

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“…That is, β-amyloid protein, tau protein, and amylin can interact synergistically, increasing to promote amyloid deposition, oxidative stress, mitochondrial dysfunction; inflammation, insulin resistance, and cell damage, culminating in dysregulation of amyloid metabolism, and glucose and neurodegeneration in AD and DM-2. In previous studies, it has been found that high plasma amylin concentration is associated with the incidence of AD, which suggests that amylin is a risk factor for AD[ 78 , 79 ]; and, amylin deposits in the brain have been found to interact with the β-amyloid protein and with tau protein in the pancreas and the hippocampus, which provides new evidence of a potential overlap between the understanding of the mechanisms of the pathophysiology of DM-2 and AD[ 80 ] (Figure 7 ).…”

Section: Amylin As a Link Between Dm-2 And Neurodegeneration: Admentioning

confidence: 99%

Cognitive disorder and dementia in type 2 diabetes mellitus

Ortíz¹,

Huerta²,

González-Usigli³

et al. 2022

WJD

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Insulin, a key pleiotropic hormone, regulates metabolism through several signaling pathways in target tissues including skeletal muscle, liver, and brain. In the brain, insulin modulates learning and memory, and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases. At the receptor level, in aging and Alzheimer’s disease (AD) models, the amount of insulin receptors and their functions are decreased. Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels. Furthermore, diabetes mellitus (DM) and insulin resistance are associated with age-related cognitive decline, increased levels of β-amyloid peptide, phosphorylation of tau protein; oxidative stress, pro-inflammatory cytokine production, and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mild obesity and insulin resistance without influencing brain size and apoptosis development. Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size and development, and contributes to behavior changes. Insulin is synthesized locally in the brain and is released from the neurons. Here, we reviewed proposed pathophysiological hypotheses to explain increased risk of dementia in the presence of DM. Regardless of the exact sequence of events leading to neurodegeneration, there is strong evidence that mitochondrial dysfunction plays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrial dysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable to those induced in wild-type mice treated with sucrose, which is consistent with the proposal that mitochondrial alterations are associated with DM and contribute to AD development. Alterations in insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidant capacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing and systemic metabolism, and could be a specific target for therapeutic strategies to decrease alterations associated with age-related cognitive decline.

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“…Cardiovascular complications affect around 65% of T2D patients despite medication and hIAPP aggregates mediates cardiotoxicity ( Despa et al, 2014 ; Rodriguez Camargo et al, 2018 ). Furthermore, T2D has been recognized as a risk factor for Alzheimer’s disease (AD) and cross-amyloid interactions between hIAPP and amyloid-β peptide (Aβ 1–42 ) have been shown to play a critical role in AD due to an increased toxicity of Aβ-IAPP hetero-oligomerization on neuronal cell membranes ( Roriz-Filho et al, 2009 ; Bharadwaj et al, 2020 ; Ly et al, 2021 ). A cross interaction between hIAPP and synuclein has been also suspected to also explain why patients with T2D are more likely to get Parkinson’s disease ( Horvath and Wittung-Stafshede, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

β-Hairpin Peptide Mimics Decrease Human Islet Amyloid Polypeptide (hIAPP) Aggregation

Lesma¹,

Bizet²,

Berardet³

et al. 2021

Front. Cell Dev. Biol.

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Amyloid diseases are degenerative pathologies, highly prevalent today because they are closely related to aging, that have in common the erroneous folding of intrinsically disordered proteins (IDPs) which aggregate and lead to cell death. Type 2 Diabetes involves a peptide called human islet amyloid polypeptide (hIAPP), which undergoes a conformational change, triggering the aggregation process leading to amyloid aggregates and fibers rich in β-sheets mainly found in the pancreas of all diabetic patients. Inhibiting the aggregation of amyloid proteins has emerged as a relevant therapeutic approach and we have recently developed the design of acyclic flexible hairpins based on peptidic recognition sequences of the amyloid β peptide (Aβ1–42) as a successful strategy to inhibit its aggregation involved in Alzheimer’s disease. The present work reports the extension of our strategy to hIAPP aggregation inhibitors. The design, synthesis, conformational analyses, and biophysical evaluations of dynamic β-hairpin like structures built on a piperidine-pyrrolidine β-turn inducer are described. By linking to this β-turn inducer three different arms (i) pentapeptide, (ii) tripeptide, and (iii) α/aza/aza/pseudotripeptide, we demonstrate that the careful selection of the peptide-based arms from the sequence of hIAPP allowed to selectively modulate its aggregation, while the peptide character can be decreased. Biophysical assays combining, Thioflavin-T fluorescence, transmission electronic microscopy, capillary electrophoresis, and mass spectrometry showed that the designed compounds inhibit both the oligomerization and the fibrillization of hIAPP. They are also capable to decrease the aggregation process in the presence of membrane models and to strongly delay the membrane-leakage induced by hIAPP. More generally, this work provides the proof of concept that our rational design is a versatile and relevant strategy for developing efficient and selective inhibitors of aggregation of amyloidogenic proteins.

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The association of circulating amylin with β‐amyloid in familial Alzheimer's disease

Cited by 27 publications

References 31 publications

Islet amyloid polypeptide cross-seeds tau and drives the neurofibrillary pathology in Alzheimer’s disease

Islet amyloid polypeptide cross-seeds tau and drives the neurofibrillary pathology in Alzheimer’s disease

Cognitive disorder and dementia in type 2 diabetes mellitus

β-Hairpin Peptide Mimics Decrease Human Islet Amyloid Polypeptide (hIAPP) Aggregation

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